The present invention relates to a new industrial process excellent in yield and purity for producing aminopiperazine derivatives and pharmaceutically acceptable salts thereof in a less number of steps with a synthetic pathway without proceeding via nitroso compounds, and is useful in a pharmaceutical field.
The process for preparing aminopiperazine derivatives of the present invention is described in an international patent application (international publication number WO91/01979) published based on the Patent Cooperation Treaty. By the said process, however, isolation and purification of intermediate products are not necessarily easy owing to water-solubility thereof or the like, so mass production of the aminopiperzine derivatives was difficult.
Additionally, the process for preparing aminopiperazine derivatives of the present invention is described in an international patent application (international publication number WO95/00502) published based on the Patent Cooperation Treaty. However, said process had many problems as an industrial synthetic process because of a large number of steps (6 steps), use of a large amount of methylene chloride as a solvent for extraction, occurrence of carcinogenic nitroso compounds as intermediates, and the necessity for reduction reaction with metallic zinc.
One object of the present invention is to provide new processes for preparing the aminopiperazine derivatives and pharmaceutically acceptable salts thereof which possess the potentiation of the cholinergic activity and are useful for treating disorders in the central nervous system, especially for treating amnesia, dementia, senile dementia, and the like in human being.
According to the present invention, the aminopiperazine derivatives of the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the following processes. 
wherein R1 is lower alkyl, aryl, ar(lower)alkoxy or heterocyclic group, each of which may be substituted with halogen, and R2 is cyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may be substituted with halogen. 
wherein R1 is lower alkyl, aryl, ar(lower)alkoxy or heterocyclic group, each of which may be substituted with halogen, and R2 is cyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may be substituted with halogen.
In the above and subsequent descriptions of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail as follows.
The term xe2x80x9clowerxe2x80x9d is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
Suitable xe2x80x9clower alkylxe2x80x9d may include a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like, in which the preferable one is methyl.
Suitable xe2x80x9carylxe2x80x9d may include phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl, and the like, in which the preferable one is phenyl or naphthyl.
Suitable xe2x80x9car(lower)alkoxyxe2x80x9d may include benzyloxy, phenethyloxy, phenylpropoxy, benzhydryloxy, trityloxy, and the like.
Suitable xe2x80x9cheterocyclic groupxe2x80x9d may include saturated or unsaturated monocyclic group containing at least one hetero-atom such as nitrogen, oxygen and sulfur atom.
Preferable xe2x80x9cheterocyclic groupxe2x80x9d thus defined may be unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazinyl, tetrazolyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, idolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s), for example, benzofuranyl, etc., and the like.
Suitable xe2x80x9ccyclo(lower)alkylxe2x80x9d may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Suitable xe2x80x9car(lower)alkylxe2x80x9d may include benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, and the like.
xe2x80x9cLower alkylxe2x80x9d, xe2x80x9carylxe2x80x9d, xe2x80x9car(lower)alkoxyxe2x80x9d, xe2x80x9cheterocyclic groupxe2x80x9d, xe2x80x9ccyclo(lower)alkylxe2x80x9d and xe2x80x9car(lower)alkylxe2x80x9d described above may be substituted with halogen [e.g. fluoro, chloro, bromo and iodo].
Pharmaceutically acceptable salts of the object compound(I) are conventional non-toxic salts and may include an acid addition salt such as an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluensulfonate etc.); a salt with an amino acid (e.g. aspartic acid salt, glutamic acid salt, etc.); and the like.
The processes for preparing the object compound(I) are explained in detail in the following.
The compound(I) or a salt thereof can be prepared by reacting the compound(III) or a salt thereof with the compound(II) or its reactive derivative at the carboxy group or a salt thereof.
Suitable salts of the compound(III) can be reffered to the ones as exemplified for the compound(I).
Suitable reactive derivative at the carboxy group of the compound (II) may include an ester, an acid halide, an acid anhydride, and the like. Suitable examples of the reactive derivatives may be an acid halide (e.g. acid chloride, acid bromide, etc.); a symmetrical acid anhydride; a mixed acid anhydride with an acid such as aliphatic carboxylic acid (e.g. acetic acid, pivalic acid, etc.), substituted phosphoric acid (e.g. dialkylphosphoric acid, diphenylphosphoric acid, etc.); an ester such as substituted or unsubstituted lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, trichloromethyl ester, etc.), substituted or unsubstituted ar(lower)alkyl ester (e.g.benzyl ester, benzhydryl ester, p-chlorobenzyl ester, etc.), substituted or unsubstituted aryl ester (e.g. phenyl ester, tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphtyl ester, etc.), or an ester with N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxy-6-chloro-1H-benzotriazole. These reactive derivatives can optionally be selected from them according to the kind of the compound (II) to be used.
In this reaction, compound (III) or a salt thereof is reacted with compound (II) or a reactive derivative at the carboxy group or a salt thereof, to form a mixed acid anhydride of compounds (III) and (II), which is then is decarbonated to form compound (I).
In this reaction, however, compound (III) may be decarbonated depending on reaction conditions to form the following compound: 
, with which compound (II) or a reactive derivative at the carboxy group or a salt thereof reacts, thus giving compound (I). This reaction is also encompassed by the process of this invention.
The process is carried out in a conventional solvent such as dioxane, chloroform, methylene chloride, tetrahydrofuran or any other conventional solvent which does not adversely influence the reaction.
When the compound (II) is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide, N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide, N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide, thionyl chloride, oxalyl chloride, lower alkoxycarbonyl halide (e.g. ethyl chloroformate, isobutyl chloformate, etc.), 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, or the like.
The reaction temperature is not critical and the reaction is usually carried out at ambient temperature or under heating.
In this reaction, compound (IV) or a salt thereof is reacted in step 1 with hypochlorite or hypobromite to form the following compound: 
or a salt thereof or the following compound: 
or a salt thereof, and this product may be isolated and then reacted in step 2 with compound (II) or a reactive derivative at the carboxy group or with a salt thereof, to give compound (I) or a salt thereof, or said product may, without being isolated, be reacted with compound (II) or a reactive derivative at the carboxy group or with a salt thereof. Each case is encompassed by the process of the present invention.
Preferable examples of hypochlorite and hypobromite include a salt with alkali metal (sodium, potassium, etc.) or with alkaline earth metal (calcium etc.).
Because step 1 proceeds in a known reaction form as Hofmann rearrangement, the reaction reagents and reaction conditions (e.g., solvent, reaction temperature, etc.) include those known to cause the Hofmann rearrangement.
Suitable reaction solvent in the reaction of step 1 is water. The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under heating.
The reaction of step 2 can be carried out in substantially the same manner as above process 1, therefore reaction reagent and reaction condition (e.g. solvent, reaction temperature, etc.) described in process 1 may be used.
The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
The compound (I) and other compounds may include more than one optical isomer due to asymmetric carbon atom(s). The isomer and mixture thereof may be included in the scope of the invention.
Further, the hydrate of compound (I) may be included in the scope of the invention.
The object compound (I) and pharmaceutically acceptable salts thereof possess a strong potentiation of the cholinergic activity and they are useful for treating disorders in the central nervous system, especially for treating amnesia, dementia, senile dementia, and the like in human being.
One object of the present invention is to provide the new processes for preparing the compound (I) or a salt thereof as described above.
The present invention is based on finding that the processes for preparing the object compound (I) and sals thereof are superior to the known processes in point of yield and purity, and further in point of a less number of steps with a synthetic pathway without proceeding via nitroso compounds.